Neovascular age-related macular degeneration (AMD), accounts for more than 85% of lost vision and involves abnormal retinal pigment epithelium (RPE), choroidal neovascularization (CNV), and photoreceptor atrophy. This research project focuses on novel cell signaling involved in pathological angiogenesis associated with neovascular AMD. We propose to study neuroprotectin Dl (NPD1), a novel stereospecific lipid mediator that displays potent anti-inflammatory actions and neuroprotective bioactivity (20,25). NPD1 is a derivative of docosahexaenoic acid(20). This fatty acid is actively recycled by RPE to, and highly enriched in, photoreceptor outer segments (16). Human RPE cells synthesize NPD1 in response to oxidative stress(24), photoreceptor outer segment phagocytosis(24), and neurotrophic factors(23). The anti-angiogenic growth factor pigment epithelium-derived factor (PEDF) is the most potent neurotrophic factor agonist for NPD1 synthesis(23). Our central hypothesis is that NPD1, a modulator of pro-inflammatory gene expression and cell survival, ameliorate CNV. Normal vasculature is regulated by pro- and anti-angiogenic factors. AMD shifts this homeostatic balance in favor of pro-angiogenic factors, resulting in choroidal neovascularization that disturbs the RPE-photoreceptor complex(36). PEDF has been shown to inhibit CNV(1,21,22) and we have demonstrated that PEDF selectively activates the synthesis of NPD1(23). Therefore, NPD1 may be a key mediator in the anti-angiogenic actions of PEDF. We propose to test the specific aims that (1) NPD1 inhibits CNV, (2) NPD1 modulates angiogenic signaling in CNV, and (3) NPD1 participates in PEDF's inhibition of CNV. Public Health Relevance: This project will elucidate inherent protective mechanisms against age-related macular degeneration and other blinding eye diseases that involve leakage of blood and fluids from uncontrolled blood vessel growth. The outcomes from this study could provide the basis of highly effective low-cost therapies for age-related macular degeneration.